Copper-Catalyzed A3-Coupling: Synthesis of 3-Amino-1,4-diynes

Article abstract of DOI:10.1002/ejoc.201600343

Cu-catalyzed A³(amine, aldehyde, and alkyne) coupling reactions were investigated for the synthesis of 3-amino-1,4-diynes. Although metal-catalyzed A³-coupling reactions have been extensively used to synthesize various propargylamine

Full text of DOI:10.1002/ejoc.201600343

DOI: 10.1002/ejoc.201600343
Communication
A3-Coupling for 3-Amino-1,4-diynes
Copper-Catalyzed A3-Coupling: Synthesis of 3-Amino-1,4-diynes
Yoon-Jeong Choi[a] and Hye-Young Jang*[a,b]
Abstract: Cu-catalyzed A3 (amine, aldehyde, and alkyne) cou- has been rarely reported. In this study, various symmetrical 3-
pling reactions were investigated for the synthesis of 3-amino- amino-1,4-diynes were synthesized by the sequential Cu-cata-
1,4-diynes. Although metal-catalyzed A3-coupling reactions lyzed dealkynylation of propargyl aldehydes followed by A3-
have been extensively used to synthesize various propargyl- coupling. Unsymmetrical 3-amino-1,4-diynes were also synthe-
amines, the A3-coupling for the synthesis of 3-amino-1,4-diynes sized in 49–85 % yields by Cu-catalyzed A3-coupling.
Introduction
Biologically and therapeutically active propargylamines includ-
ing enantioselective variants have been synthesized by various
reactions.[1–5] One of the known methods for the synthesis of
propargylamines involves the metal-catalyzed alkyne addition
to imines or in situ formed imines derived from amines and
aldehydes (A3-coupling), where Cu, Au, and Ag catalysts are of-
ten used. However, similar metal-catalyzed addition reactions
have been rarely reported for the synthesis of 3-amino-1,4-di-
ynes.[6] These are generally synthesized by the reaction of alk-
yne anions with thioiminium compounds, formamide acetals,
and aminals (Scheme 1).[7,8] In these reactions, stoichiometric
amounts of organometallic reagents (e.g., alkyllithium and Gri-
gnard reagents) are used to generate the alkyne anions. Cata-
lytic methods for adding alkynes to such electrophiles have
Scheme 1. Synthesis of 3-amino-1,4-diynes.
been rarely reported.[7d]
We have been interested in the use of propargyl aldehydes
in Cu-catalyzed reactions.[9] In the presence of Cu catalysts,
propargyl aldehydes undergo dealkynylation to afford Cu–alk-
yne intermediates; subsequent addition to in situ generated
propargyl imines provides 3-amino-1,4-diynes. Using this three-
component coupling of aldehydes, alkynes, and amines (A3-
coupling),[3,4] symmetrical 3-amino-1,4-diynes were synthesized
as shown in Scheme 1. Unsymmetrical 3-amino-1,4-diynes were
also synthesized by adding extra alkynes along with propargyl
aldehydes and amines. In this study, we have shown two cop-
per-catalyzed reaction protocols for the synthesis of 3-amino-
1,4-diynes; copper-catalyzed dealkynylation followed by A3-
coupling and copper-catalyzed A3-coupling. Detailed optimiza-
tion conditions and a reaction mechanism are presented.
Results and Discussion
First, we investigated the reaction of phenylpropargyl aldehyde
and morpholine in the presence of 10 mol-% CuI (Table 1). Sym-
metrical 3-amino-1,4-diynes 1 were obtained in 7–66 % yields
in various solvents (such as toluene, ethyl acetate, acetonitrile,
THF, and dioxane) (Table 1, Entries 1–6). To evaluate the effect
of ligands on the catalytic activity, various ligands such as 1,10-
phenanthroline (1,10-phen), 2,2′-bipyridine (2,2′-bipy), bis(2,6-
diisopropylphenyl)imidazol-2-ylidene (IPr), 1,3-bis(diphenyl-
phosphino)propane (dppp), and PPh3 were investigated; the
monodentate ligand PPh3 showed the best result (Entries 6–
11). The nitrogen-donor ligands (1,10-phen and 2,2′-bipy) and
carbene ligand (IPr) decreased the yield of 1 (Entries 7–9). When
the catalyst CuI was replaced by other Cu salts such as CuCl,
CuBr, CuBr2, and Cu(OTf)2, 55 %, 67 %, 55 %, and 16 % yields,
respectively, were obtained (Entries 12–15). In the absence of
oxygen, 1 was obtained in 76 % yield, a slightly lower yield than
that obtained in Entry 11. In addition to the desired process
forming 2-amino-1,4-diynes, the oxidative dimerization of
phenylacetylene (Glaser coupling) also takes place to afford di-
phenylbutadiyne. Reduced copper catalysts from Glaser cou-
[a] Division of Energy Systems Research, Ajou University
Suwon, Korea
E-mail: hyjang2@ajou.ac.kr
http://ajou.ac.kr/~hyjang2
[b] Korea Carbon Capture & Sequestration R&D Center,
Deajeon 305-343, Korea
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600343.
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Communication
pling need to be oxidized by oxygen, which is the reason to
run these reactions in the presence of oxygen.
Table 2. Examples of symmetrical 3-amino-1,4-diynes.
Table 1. Optimization of the synthesis of 1.
[a] 0.5 mmol of aldehyde and 0.5 mmol of amine. [b] The reaction was run
at room temperature.
absence of oxygen to provide 8 in 27 % and 29 %, respectively.
Upon the addition of different alkynes, various unsymmetrical
3-amino-1,4-diynes 9, 10, and 11 were obtained in 75 %, 67 %,
and 85 % yields, respectively (Entries 2–4). Instead of phenyl-
propargyl aldehyde, aliphatic propargyl aldehydes participated
in the reaction with phenylacetylene and morpholine, to afford
the desired products in good yields (Entries 5–8). The reaction
of dec-2-ynal with ethynylcyclohex-1-ene gave product 12 in
81 % yield (Entry 9). The reactions of 1-phenylpiperazine and N-
benzylmethylamine furnished unsymmetrical 3-amino-1,4-di-
ynes 13 and 14 in 65 % and 49 % yields, respectively (Entries 10
and 11).
[a] 0.5 mmol of aldehyde and 0.5 mmol of amine. [b] The reaction was run
in the absence of O2.
Next, the substrate scope of the reaction was examined
(Table 2). Methoxy- and methyl-substituted phenylpropargyl
aldehydes were converted into products 2 and 3 in 68 % and
73 % yields, respectively (Entries 1 and 2). The reaction of an
aliphatic propargyl aldehyde afforded product 4 in 34 % yield
(Entry 3). Presumably, the dealkynylation of aliphatic propargyl
aldehydes to Cu–alkyne species is not as effective as that of
aromatic propargyl aldehydes. Cyclohexenylpropargyl aldehyde
also participated in the reaction to afford product 5 in 78 %
yield (Entry 4). Piperidine and N-benzylmethylamine partici-
pated in the reaction to produce the desired products 6 and 7,
respectively (Entries 5 and 6).
Table 3. Examples of unsymmetrical 3-amino-1,4-diynes.
Next, we investigated if it is possible to obtain unsymmetri-
cal 3-amino-1,4-diynes using the Cu-catalyzed A3-coupling of
propargyl aldehydes, alkynes, and amines. Pleasingly, the addi-
tion of an extra alkyne to the reaction mixture provided unsym-
metrical 3-amino-1,4-diynes (Table 3). The three-component re-
action of phenylpropargyl aldehyde, cyclohexylalkyne, and
morpholine afforded the cross-coupling product 8 in good yield
(Entry 1). In contrast to the synthesis of symmetrical diynes, the
Cu-catalyzed dealkynylation of propargyl aldehydes was sup-
pressed in the synthesis of unsymmetrical diynes.[10] The reac-
tion in the absence of oxygen was run to give a lower yield
(66 %), which was explained in Table 1. In addition to Cu salts
as the catalysts, other metal salts such as AuI, AuIII, PtIV, and PtII
[a] 0.75 mmol of aldehyde, 0.5 mmol of amine, and 0.75 mmol of acetylene.
[b] The reaction was run in the absence of O2. [c] Without PPh3. [d] At room
temperature.
A possible catalytic cycle for the formation of symmetrical 3-
were investigated. Compound 8 was obtained in 21 % (AuCl3), amino-1,4-diynes is shown in Scheme 2. Based on the previous
25 % [AuCl(PPh3)], 7 % (PtCl4), and 9 % (PtCl2) yields. Because report,[9a] the copper-catalyzed dealkynylation of phenylprop-
the gold-catalyzed A3-coupling is sensitive to oxygen, AuCl3- argyl aldehydes occurs via hemiaminal intermediate I to afford
and AuCl(PPh3)-catalyzed reactions were also conducted in the alkynyl–copper species II, which reacts with iminium salts
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formed from phenylpropargyl aldehydes and amines to provide 2015M1A8A1048886), and the C1 Gas Refinery Program (no.
the desired symmetrical 3-amino-1,4-diynes.
2015M3D3A1A01065436) through the National Research Foun-
dation of Korea (NRF).
Keywords: A3-coupling · Aldehydes · Alkynes · 3-Amino-1,4-
diynes · Copper catalysts · Propargyl aldehydes
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Scheme 2. Plausible reaction mechanism for the synthesis of symmetrical 3-
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Conclusions
A simple and efficient Cu-catalyzed A3-coupling reaction was
developed for the synthesis of symmetrical and unsymmetrical
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Experimental Section
General Procedure for the Synthesis of Symmetrical 3-Amino-
1,4-diynes: A solution of phenylpropargyl aldehyde (65.1 mg,
0.5 mmol), morpholine (43.6 mg, 0.5 mmol), copper(I) iodide
(9.5 mg, 0.05 mmol) and triphenylphosphine (13.1 mg, 0.05 mmol)
in dichloroethane (0.5 M) was in a 5 mL round-bottomed flask and
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was stirred under O2 at 80 °C for 18 h. The solvent was evaporated,
and the reaction mixture was purified by silica gel flash column
chromatography (3 % ethyl acetate/hexane) to afford 1 (58.8 mg,
78 %).
General Procedure for the Synthesis of Unsymmetrical 3-
Amino-1,4-diynes:
A solution of phenylpropargyl aldehyde
(97.6 mg, 0.75 mmol), morpholine (43.6 mg, 0.5 mmol), cyclohexyl-
acetylene (81.1 mg, 0.75 mmol), copper(I) iodide (9.5 mg,
0.05 mmol) and triphenylphosphine (13.1 mg, 0.05 mmol) in di-
[6] While we were preparing this manuscript, this article was published:
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2150–2153.
chloroethane (0.5
M) in a 5 mL round-bottomed flask was stirred
under O2 at 80 °C for 18 h. The solvent was evaporated, and the
reaction mixture was purified by silica gel flash column chromatog-
raphy (3 % ethyl acetate/hexane) to afford 8 (112.2 mg, 73 %).
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Acknowledgments
This study was supported by the Korea Research Foundation
(no. 2013008819), the Korea CCS R&D Center (KCRC) (no.
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Received: March 20, 2016
Published Online: ■
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Communication
A3-Coupling for 3-Amino-1,4-di-
ynes
Y.-J. Choi, H.-Y. Jang* ........................ 1–5
Copper-Catalyzed A3-Coupling: Syn-
thesis of 3-Amino-1,4-diynes
Symmetrical and unsymmetrical 3- involved in the dealkynylation of prop-
amino-1,4-diynes are synthesized by argyl aldehydes and the A3-coupling
copper-catalyzed coupling of prop- reaction.
argyl aldehydes. Copper catalysts are
DOI: 10.1002/ejoc.201600343
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